Time course of AQP-2 and ENaC regulation in the kidney in response to PPAR agonists associated with marked edema in rats

Tiwari, Swasti; Blasi, Eileen; Heyen, Jonathan R.; McHarg, Aileen; Ecelbarger, Carolyn M.

doi:10.1016/j.phrs.2008.03.013

Cited by 29 publications

(32 citation statements)

References 45 publications

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“…51 Changes in fluid retention have been linked to PPARg-mediated changes in salt absorption and aquaporin protein expression in renal tubule epithelial cells. 29,52,53 When used in our POD-ATTAC model, adiponectin serum levels were significantly elevated. After podocyte loss-just as in untreated mice-PPARg agonisttreated mice exhibited massive albuminuria.…”

Section: Discussionmentioning

confidence: 87%

“…28,29,50 These drugs have been prescribed to treat type 2 diabetes with great success, although the adverse effect of fluid retention or edema may be linked to some cardiovascular complications with the drugs. 51 Changes in fluid retention have been linked to PPARg-mediated changes in salt absorption and aquaporin protein expression in renal tubule epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…The absence of adiponectin in the KO animals probably unmasked yet-unidentified renal changes with PPARg agonist use. 29 Trichrome staining revealed marked fibrosis at 28 days in both POD and POD-KO mice treated with PPARg agonists ( Figure 6F). Fibrosis in COOH-treated POD-KO mice was worsened, as expected, at days 28 and 60 (F[2,10]=8.226, P=0.008).…”

Section: Adiponectin Overexpression Limits Renal Fibrosis After Podocmentioning

confidence: 99%

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Adiponectin Promotes Functional Recovery after Podocyte Ablation

Rutkowski

Wang²,

Park

et al. 2013

Journal of the American Society of Nephrology

134

115

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Low levels of the adipocyte-secreted protein adiponectin correlate with albuminuria in both mice and humans, but whether adiponectin has a causative role in modulating renal disease is unknown. Here, we first generated a mouse model that allows induction of caspase-8-mediated apoptosis specifically in podocytes upon injection of a construct-specific agent. These POD-ATTAC mice exhibited significant kidney damage, mimicking aspects of human renal disease, such as foot process effacement, mesangial expansion, and glomerulosclerosis. After the initial induction, both podocytes and filtration function recovered. Next, we crossed POD-ATTAC mice with mice lacking or overexpressing adiponectin. POD-ATTAC mice lacking adiponectin developed irreversible albuminuria and renal failure; conversely, POD-ATTAC mice overexpressing adiponectin recovered more rapidly and exhibited less interstitial fibrosis. In conclusion, these results suggest that adiponectin is a renoprotective protein after podocyte injury. Furthermore, the POD-ATTAC mouse provides a platform for further studies, allowing precise timing of podocyte injury and regeneration.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Adiponectin Overexpression Limits Renal Fibrosis After Podocmentioning

confidence: 99%

See 1 more Smart Citation

Adiponectin Promotes Functional Recovery after Podocyte Ablation

Rutkowski

Wang²,

Park

et al. 2013

Journal of the American Society of Nephrology

134

115

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“…These findings suggest that increased Na ϩ and water reabsorption in multiple nephron segments may contribute to TZD-induced fluid retention. However, when TZDs were administered for longer than 5 days, renal expression of nonglycosylated form of AQP2 (26) and all three subunits of ENaC (5) was significantly downregulated, coinciding with normal urine volume. Therefore, the later reduction of AQP2 and ENaC is considered as adaptive response to reestablish Na ϩ and water balance.…”

Section: Discussionmentioning

confidence: 99%

Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters

Zhou

Liu

Jia

et al. 2013

American Journal of Physiology-Renal Physiology

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T. Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters. Am J Physiol Renal Physiol 305: F1491-F1497, 2013. First published September 4, 2013 doi:10.1152/ajprenal.00004.2013, which are synthetic peroxisome proliferator-activated receptor subtype-␥ (PPAR␥), agonists are highly effective for treatment of type 2 diabetes. However, the side effect of fluid retention has significantly limited their application. Most of the previous studies addressing TZD-induced fluid retention employed healthy animals. The underlying mechanism of this phenomenon is still incompletely understood, particularly in the setting of disease state. The present study was undertaken to examine rosiglitazone (RGZ)-induced fluid retention in db/db mice and to further investigate the underlying mechanism. In response to RGZ treatment, db/db mice exhibited an accelerated plasma volume expansion as assessed by hematocrit (Hct) and fluorescent nanoparticles, in parallel with a greater increase in body weight, compared with lean controls. In response to RGZ-induced fluid retention, urinary Na ϩ excretion and urine volume were significantly increased in lean mice. In contrast, the natriuretic and diuretic responses were significantly blunted in db/db mice. RGZ db/db mice exhibited a parallel decrease in plasma Na ϩ concentration and plasma osmolality, contrasting to unchanged levels in lean controls. Imunoblotting analysis showed downregulation of renal aquaporin (AQP) 2 expression in response to RGZ treatment in lean mice but not in db/db mice. Renal AQP3 protein expression was unaffected by RGZ treatment in lean mice but was elevated in db/db mice. In contrast, the expression of Na ϩ /H ϩ exchanger-3 (NHE3) and NKCC2 was unchanged in either mouse strain. Together these results suggest that compared with the lean controls, db/db mice exhibited accelerated plasma volume expansion that was in part due to the inappropriate response of renal water transporters. db/db; nanoparticle; plasma volume; PPAR␥; rosiglitazone THE PEROXISOME PROLIFERATOR-activated receptor subtype-␥ (PPAR␥) ligands, the synthetic insulin-sensitizing thiazolidinediones (TZD) compounds, are used for glycemic control in patients with diabetes mellitus (13). Currently, two TZDs, rosiglitazone (RGZ) and pioglitazone, are available, since RGZ was withdrawn from the market in Europe and its use is restricted in the United States due to concerns about the increased risk of myocardial infarction in several clinical trials (18). TZDs lower blood glucose by increasing insulin sensitivity, improving lipid profile, attenuating microalbuminuria, decreasing blood pressure, and inhibiting inflammation in animal models and diabetic patients (6,10,14). Despite the favorable effect on glycemic control, these agents are associated with body weight gain and fluid retention, which is presented as edema in extremities in at least 5% of patients and can progress to pulmonary edema and congestive heart failure (4, 20,...

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“…The contradictory results illustrate the complexity of glitazone-induced sodium reabsorption. Although rapid activation of renal sodium transporters may occur, compensatory or escape mechanisms may take place with time [25], either through the downregulation of sodium transporters or through the increase in natriuretic peptides. The inability to activate the compensatory mechanisms or concurrent treatment with insulin may alter these compensatory mechanisms and enhance fluid retention.…”

Section: Discussionmentioning

confidence: 99%

Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals

et al. 2010

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Aims/hypothesis Glitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes. Their use is, however, associated with fluid retention and an increased risk of congestive heart failure. We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers. This study examines the effects of pioglitazone on renal sodium handling in individuals prone to insulin resistance, i.e. those with diabetes and/or hypertension. Methods In this double-blind randomised placebo-controlled four-way crossover study, we examined the effects of pioglitazone (45 mg daily during 6 weeks) or placebo on renal, systemic and hormonal responses to changes in sodium intake in 16 individuals, eight with type 2 diabetes and eight with hypertension. Results Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption, without any change in renal haemodynamics or in the modulation of the renin-angiotensin aldosterone system to changes in salt intake. A compensatory increase in brain natriuretic peptide levels was observed. In spite of sodium retention, pioglitazone dissociated the bloodpressure response to salt and abolished salt sensitivity in salt-sensitive individuals. Conclusions/interpretation Pioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals. These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones.

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Time course of AQP-2 and ENaC regulation in the kidney in response to PPAR agonists associated with marked edema in rats

Cited by 29 publications

References 45 publications

Adiponectin Promotes Functional Recovery after Podocyte Ablation

Adiponectin Promotes Functional Recovery after Podocyte Ablation

Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters

Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals

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